Micro RNA ‐31 is a positive modulator of endothelial–mesenchymal transition and associated secretory phenotype induced by TGF ‐β

Transforming growth factor‐β ( TGF ‐β) plays central roles in endothelial–mesenchymal transition (End MT ) involved in development and pathogenesis. Although End MT and epithelial–mesenchymal transition are similar processes, roles of micro RNA s in End MT are largely unknown. Here, we report that constitutively active micro RNA ‐31 (miR‐31) is a positive regulator of TGF ‐β‐induced End MT . Although the expression is not induced by TGF ‐β, miR‐31 is required for induction of mesenchymal genes including α‐ SMA , actin reorganization and MRTF ‐A activation during End MT . We identified VAV 3, a regulator of actin remodeling and MRTF ‐A activity, as a miR‐31 target. Global transcriptome analysis further showed that miR‐31 positively regulates End MT ‐associated unique secretory phenotype (End MT ‐ SP ) characterized by induction of multiple inflammatory chemokines and cytokines including CCL 17, CX 3 CL 1, CXCL 16, IL ‐6 and Angptl2. As a mechanism for this phenomenon, TGF ‐β and miR‐31 suppress Stk40, a negative regulator of NF ‐κB pathway. Interestingly, TGF ‐β induces alternative polyadenylation ( APA )‐coupled miR‐31‐dependent Stk40 suppression without concomitant miR‐31 induction, and APA ‐mediated exclusion of internal poly(A) sequence in Stk40 3′ UTR enhances target efficiency of Stk40. Finally, miR‐31 functions as a molecular hub to integrate TGF ‐β and TNF ‐α signaling to enhance End MT . These data confirm that constitutively active micro RNA s, as well as inducible micro RNA s, serve as phenotypic modifiers interconnected with transcriptome dynamics during End MT .